mastocytosis

Clonal mast cell neoplasm driven by activating KIT mutations (D816V in >85% of adults). Spectrum ranges from skin-limited disease (cutaneous mastocytosis) to indolent systemic mastocytosis (ISM, near-normal life expectancy) to aggressive subtypes (ASM, mast cell leukaemia). The IM resident’s role: recognise it, confirm with tryptase + KIT mutation testing, stratify subtype, and manage mediator symptoms — cytoreductive therapy is haematology-driven.

quick recognition

recurrent unexplained anaphylaxis — especially to hymenoptera stings, especially without urticaria
flushing + GI symptoms + hypotension in clusters
urticaria pigmentosa — hyperpigmented macules/papules that urticate on stroking (Darier’s sign)
unexplained osteoporosis in a young patient
baseline serum tryptase persistently >20 ng/mL
anaphylaxis + tryptase >11.4 ng/mL even between episodes → investigate

classification

cutaneous mastocytosis (CM)

Subtype	Features
maculopapular CM (urticaria pigmentosa)	most common; pigmented macules/papules, positive Darier’s sign
diffuse CM	diffusely thickened skin; may blister; mainly children
solitary mastocytoma	single nodule; infants; usually self-resolves

CM in children is common and often self-resolves by puberty
CM in adults usually reflects underlying systemic disease → bone marrow biopsy

systemic mastocytosis (SM) — WHO 5th edition

Subtype	Key features
indolent SM (ISM)	most common; ≤1 B-finding, no C-findings; near-normal life expectancy
bone marrow mastocytosis (BMM)	SM criteria met, no skin lesions, no B-findings, tryptase often <125 ng/mL
smouldering SM (SSM)	≥2 B-findings, no C-findings; ~7% progress to advanced SM
aggressive SM (ASM)	≥1 C-finding (organ damage)
SM with associated haematological neoplasm (SM-AHN)	SM + MDS, MPN, AML, etc.
mast cell leukaemia (MCL)	≥20% mast cells on marrow aspirate; poor prognosis

B-findings (burden) and C-findings (cytopenia/organ damage)

B-findings (high mast cell burden):

bone marrow biopsy >30% mast cell infiltration
tryptase >200 ng/mL
hepatosplenomegaly without organ dysfunction

C-findings (organ damage from mast cell infiltration):

cytopaenias (ANC <1.0, Hb <100, platelets <100)
hepatomegaly with impaired liver function ± ascites
splenomegaly with hypersplenism
malabsorption with weight loss
large osteolytic lesions ± pathologic fractures

diagnosis

WHO criteria for systemic mastocytosis

1 major + 1 minor, or ≥3 minor criteria

	Criterion
major	multifocal dense mast cell infiltrates (≥15 in aggregates) on bone marrow or extracutaneous biopsy
minor 1	>25% of mast cells are spindle-shaped or atypical
minor 2	aberrant CD25 ± CD2 ± CD30 on mast cells (in addition to CD117)
minor 3	KIT D816V (or other activating KIT mutation)
minor 4	baseline tryptase >20 ng/mL (does not count if associated myeloid neoplasm present; adjust for hereditary alpha-tryptasaemia)

workup

serum tryptase — basal level; >20 ng/mL is a minor criterion
KIT D816V — high-sensitivity testing (ASO-qPCR or ddPCR); test peripheral blood first → bone marrow if negative
bone marrow biopsy — with flow cytometry (CD117, CD25, CD2, CD30) and IHC (tryptase, CD117, CD25)
CBC, comprehensive metabolic panel, LDH
DEXA scan — osteoporosis is common and under-recognised
CT abdomen/pelvis — hepatosplenomegaly assessment
if eosinophilia present and KIT D816V negative → screen for FIP1L1::PDGFRA
advanced SM → NGS panel (ASXL1, RUNX1, SRSF2, NRAS) for prognostication

tryptase interpretation

Hereditary alpha-tryptasaemia (extra TPSAB1 copies) → elevated baseline tryptase without mastocytosis. Prevalence ~5%. Consider if tryptase is mildly elevated (20–40 ng/mL) without other SM features. Genetic testing available.

management

ISM/SSM — symptom-directed

Step 1: H1 + H2 antihistamines (scheduled ± PRN)

Step 2: add leukotriene receptor antagonist, cromolyn sodium, PPI

Step 3: omalizumab — particularly for recurrent anaphylaxis or refractory mediator symptoms

Bone disease: bisphosphonates or denosumab

Anaphylaxis prevention:

carry 2 epinephrine autoinjectors at all times
venom immunotherapy for hymenoptera-allergic patients — lifelong (do not discontinue)
perioperative: premedicate with H1 + H2 blockers ± corticosteroids; alert anaesthesia

Cytoreduction for symptomatic ISM: avapritinib (selective KIT D816V inhibitor) — if platelets ≥50 × 10⁹/L and refractory to anti-mediator therapy

triggers to counsel patients about

Hymenoptera stings, alcohol, extreme temperatures, NSAIDs (variable — not a universal trigger), opioids, radiocontrast, physical exertion, emotional stress. Provide written trigger avoidance plan.

advanced SM (ASM, SM-AHN, MCL) — cytoreductive therapy

preferred: avapritinib (platelets ≥50 × 10⁹/L) or midostaurin
other: cladribine (rapid debulking), peginterferon alfa-2a ± prednisone
imatinib: only if non-D816V KIT mutation (rare — D816V is imatinib-resistant)
allogeneic HCT: refractory advanced SM or SM-AHN with aggressive myeloid component

imatinib does not work for D816V

KIT D816V confers imatinib resistance. Imatinib is only useful for the rare non-D816V transmembrane mutations (e.g., F522C, K509I). Avapritinib and midostaurin are effective against D816V.

what NOT to do

do not dismiss recurrent anaphylaxis without checking a baseline tryptase
do not diagnose “mast cell activation syndrome” without first excluding systemic mastocytosis
do not use imatinib for D816V-positive SM
do not stop venom immunotherapy in mastocytosis patients (lifelong indication)
do not assume CM in adults is benign — always investigate for systemic disease

prognosis

Subtype	Median survival
ISM	near-normal life expectancy; 1–3% progress to advanced SM
SSM	good; ~7% progress to advanced SM
ASM	significantly reduced; varies with mutation profile
SM-AHN	depends on associated neoplasm
MCL	poor — months without treatment

High-risk mutations (ASXL1, RUNX1, SRSF2) → worse prognosis across all advanced subtypes.